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The Twists and Turns of Life: Supramolecular Chemistry

Anne Petitjean

Photo: Bernard Clark

Chemist Anne Petitjean rhymes off her childhood influences with ease − the work of Louis Pasteur, a desire to be an artist, and a need to answer life’s mysteries from the “bottom up.” She found convergence of these interests in supramolecular chemistry, a field she describes as “molecular sociology … how [molecules] behave together, the way they interact, the way they feel each other, recognize each other, sense each other.” The field applies to everything from materials science to medicine and environmental studies.

Like Pasteur, Petitjean’s approach to research is “to feel what society needs and be aware of where your chemistry takes you.” One of her favourite targets is DNA, which has the most predictable structure of the large, biologically important molecules. Most DNA molecules at rest in our cells have a double helix shape – with pairs of nucleic acids arranged in a twisting ladder. The arrangement is compact and keeps our genetic material safe, buried inside the helix.

But cells are dynamic and when DNA’s information is read, the molecule’s architecture transforms into folds, loops, and other secondary structures. It is these temporary structures Petitjean finds most interesting for they are “responsible for life.” Her favourite secondary structures are the guanine quadruplexes. Guanine is one of four nucleic acids in DNA, and it forms quartets – squares that lie flat, stacked like pancakes, turning a section of the DNA ladder into a wide staircase. With 23 known structural variations and a number of specific functions, Petitjean is revelling in quadruplex mysteries.

Telomeres, the ends of chromosomes, are comprised of these quadruplexes, but they occur along the DNA strands as well. Petitjean thinks they play a major role in pacing DNA processing by creating a “bulge” that stalls proteins reading a strand. The proteins cannot progress past a quadruplex bulge, so reading of the DNA stops, and gene expression is prevented.

Quadruplex folding differs between healthy and cancerous cells, so targeting quadruplexes is one anti-cancer strategy. In normal chromosomes, telomeres are chopped down a little after each replication. When the telomere becomes too short, the cell ceases to divide. In cancer cells, the telomeres elongate again after replication and division never stops. Petitjean’s lab has created a small molecule that interacts with telomere quadruplexes, preventing elongation, and slowing down cancer. However, the lab has accidentally discovered that exposing DNA to this manufactured molecule and X-ray radiation does more than slow down cancer cells, it kills them. Petitjean is not sure why the combo is effective, but it might have to do with their invented molecule interacting with quadruplex folding along DNA strands, preventing repair, and thus enhancing radiation’s effcacy.

Accidental discoveries like this seem to be commonplace in Petitjean’s lab, though it is not just luck but open-mindedness that contributes to the revelations. Petitjean says, “In science, you start with a hypothesis, it takes you maybe to where you thought you were going, but most often it takes you somewhere else.”

Another unplanned line of inquiry pursued by Petitjean started with a molecule made while “playing” in the lab. The molecule has a tiny pore, and Petitjean was quick to take note that the pore is the size of a calcium ion. In solution, they tested to see if calcium interacts with the molecule. They were not disappointed. Not only does the molecule bind to calcium, but it also likes to “align itself in a regular cylinder.” What they’ve made is a channel for calcium. Now they’re working on whether this molecule can self-assemble as a channel in a cell’s membrane. Such calcium ion channels function in the body to control the influx of calcium into cells, particularly in muscle and nerve tissues. It is Petitjean’s hope that this artificial calcium channel might someday have applications in medicine. With discoveries like these, Petitjean’s childhood hero, Pasteur, would be pleased at how well she embodies his famous words, “chance favours the prepared mind.”